Cancer cells consume more nutrients and energy than non-malignant cells due to altered metabolisms (Koppenol, et al., Otto Warburg's contributions to current concepts of cancer metabolism, Nat Rev Cancer 11, 325-337 (2011)). Elevated aerobic glycolysis/fermentation, called the Warburg effect, is commonly used by cancer cells for sustaining growth and survival (Ferreira, L. M., Cancer metabolism: the Warburg effect today, Exp Mol. Pathol. 89, 372-380 (2010)). Amino acids, such as glutamine, can be abducted for energy production when glucose is not sufficiently available (DeBerardinis, et al., Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis, Proc. Nat'l Acad. Sci. USA 104, 19345-19350 (2007)). Enhanced oxidation of branched chain amino acids (BCAA), valine, leucine and isoleucine, occurs in cancers at late stage (Baracos, et al., Investigations of branched-chain amino acids and their metabolites in animal models of cancer, J. Nutr. 136, 237S-242S (2006); Beck, et al., Nitrogen excretion in cancer cachexia and its modification by a high fat diet in mice, Cancer Res. 49, 3800-3804 (1989); Pisters, et al., Protein and amino acid metabolism in cancer cachexia: investigative techniques and therapeutic interventions, Crit. Rev. Clin. Lab. Sci. 30, 223-272 (1993)). The driving force of altered metabolisms in cancer remains unclear. One possible cause is intrinsic, such as the malignant tumor cells' high demand for energy and building blocks, including amino acids for protein synthesis, nucleic acids for DNA and RNA syntheses, and fatty acids for membranous structures (Vander et al., Understanding the Warburg effect: the metabolic requirements of cell proliferation, Sci. 324, 1029-1033 (2009)). In support of this theory, it has recently been found that upregulation of an ATP hydrolase, ectonucleoside triphosphate diphosphohydrolase 5—which is induced by the PI3K pathway that promotes cell proliferation and survival—enhances cancer metabolism (Fang, M., et al., The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway, Cell 143, 711-724 (2010)).
Another possible cause is extrinsic, such as tissue environmental pressure, including hypoxia and ectopic microenvironment of the host organ of metastasis to which metastatic cancer cells have to adapt for survival and growth (Fidler, I. J., The organ microenvironment and cancer metastasis, Differentiation 70, 498-505 (2002); Langley, R. R. & Fidler, I. J. The seed and soil hypothesis revisited—the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128, 2527-2535 (2011); Martinez-Outschoorn, U. E., et al., Stromal-epithelial metabolic coupling in cancer: Integrating autophagy and metabolism in the tumor microenvironment, Int. J. Biochem. Cell Biol. 43, 1045-1051 (2011)). The microenvironment of different tissues differs significantly. Metastatic tumor cells can reach many organs, but grow in only specific organs (Fidler, I. J., The organ microenvironment and cancer metastasis, Differentiation 70, 498-505 (2002)). The compatibility between tumor cells and the microenvironment of host tissue determines the outcome of metastasis. For example, studies have shown that cancer associated stromal cells are reprogrammed in favor of metabolizing lactate extruded by cancer cells (Martinez-Outschoorn, U. E., et al., Stromal-epithelial metabolic coupling in cancer: Integrating autophagy and metabolism in the tumor microenvironment, Int. J. Biochem. Cell Biol. 43, 1045-1051 (2011)).
Breast cancer is one of the most common tumors that present with brain metastasis, a late complication of progressive metastatic disease for which effective treatment options are limited. The microenvironment of the brain plays a key role in the development of the therapeutic resistance of brain metastasis (Steeg, P. S., Camphausen, K. A. & Smith, Q. R. Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 11, 352-363 (2011)). The interstitial space of the brain is characterized by low levels of glucose (Fellows, L. K., et al., Extracellular brain glucose levels reflect local neuronal activity: a microdialysis study in awake, freely moving rats, J. Neurochem. 59, 2141-2147 (1992); Hu, Y. et al., Rapid changes in local extracellular rat brain glucose observed with an in vivo glucose sensor, J. Neurochem. 68, 1745-1752 (1997)), high levels of glutamine (Yudkoff, M., et al., Brain glutamate metabolism: neuronal-astroglial relationships, Dev. Neurosci. 15, 343-350 (1993)), and an intermediate metabolite of BCAAs, the branched chain alpha-ketoacids (BCKA) (Yudkoff, M., Brain metabolism of branched-chain amino acids, Glia 21, 92-98 (1997)). Glutamine and BCAAs can serve as energy substrates (Daikhin, Y. et al., Compartmentation of brain glutamate metabolism in neurons and glia, J. Nutr. 130, 1026S-1031S (2000)). The rich contents of glutamine and BCAAs in the interstitial microenvironment may contribute to the survival of cancer cells growing in the brain. Expressions of mRNA of glycolytic enzymes were found to be increased in the brain metastatic breast cancer cells (Harris, R. A. et al., Overview of the molecular and biochemical basis of branched-chain amino acid catabolism, J. Nutr. 135, 1527S-1530S (2005)); however, the role of carbon sources other than glucose for the survival/growth of brain metastatic breast cancer cells remains to be investigated. Because brain metastatic breast cancer cells (and some other cancer cells) are able to thrive in glucose-free medium, those cells are resistant to contemporary cancer therapies that target glucose pathways. Therefore, there is a need in the art for methods of treating cancer cells that survive in glucose-independent conditions.